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Published ahead of print on August 18, 2004, doi:10.1164/rccm.200312-1668OC

Am. J. Respir. Crit. Care Med., Volume 170, Number 10, November 2004, 1101-1107

A more recent version of this article appeared on November 15, 2004
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Submitted on December 8, 2003
Accepted on August 16, 2004

Bosentan Inhibits Transient Receptor Potential Channel Expression in Pulmonary Vascular Myocytes

Naomi Kunichika1, Judd W Landsberg1, Ying Yu1, Hideki Kunichika1, Patricia A Thistlethwaite1, Lewis J Rubin1, and Jason X-J Yuan1*

1 Departments of Medicine and Surgery, University of California, San Diego, La Jolla, CA, USA

* To whom correspondence should be addressed. E-mail: xiyuan{at}ucsd.edu.

Bosentan, a dual endothelin receptor blocker, has been used clinically to treat idiopathic pulmonary arterial hypertension (IPAH). However, the mechanism of its antiproliferative effect on pulmonary artery smooth muscle cells (PASMC) remains unclear. A rise in cytoplasmic Ca2+ stimulates PASMC proliferation, and the canonical transient receptor potential (TRPC) channels are an important pathway for Ca2+ entry during PASMC proliferation. Bosentan (20-50 µM) significantly inhibited endothelin-1- or platelet-derived growth factor (PDGF)-mediated PASMC growth and 3H-thymidine uptake. In PASMC, endothelin-1 (1 µM) and PDGF (10 ng/ml) both upregulated protein expression of TRPC6, whereas bosentan markedly downregulated TRPC6 protein levels. Furthermore, TRPC6 expression in PASMC from IPAH patients was greater than in normal PASMC, and the antiproliferative effect of bosentan was significantly enhanced in IPAH-PASMC in comparison to normal PASMC. These observations demonstrate that the antiproliferative effect of bosentan on PASMC involves the downregulation of TRPC6 channels via a mechanism possibly independent of endothelin receptor blockade. The greater effect of bosentan on IPAH-PASMC than on normal PASMC suggest that increased TRPC6 expression and function may be involved in the overgrowth of PASMC in IPAH patients.
Key words: endothelin-1, Ca2+ channels, transient receptor potential cation channels




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